Colorectal cancer remains a pre-eminent health concern in the United States today and is increasing in incidence worldwide. While chemotherapy for colon cancer is virtually standardized in this country (5-fluorouracil (FUra) and leucovorin), the reasons for only a 30-40% response rate are poorly understood. One highly under-explored variable in cancer chemotherapy is the effect of the patient's nutrient or dietary profile at the initiation of therapy and duration throughout therapy; dietary modification may significantly alter chemotherapeutic response. This project focuses on devising methods to prevent, treat, and control the development and progression of colorectal cancer. The novel approach to be explored in this project combines standard chemotherapeutic treatment with diet and nutrition modification to maximize drug efficacy thereby maintaining balances between key biochemical events that regulate cellular growth and differentiation. To date, very little research has examined the impact of dietary modulation on drug efficacy. This project will explore the effects of modifying the dietary environment in improving the response to FUra in a human colon cell culture system and the Ape Min/+ mouse model. Recent experiments in mice have shown that a diet high in fat, and low in vitamin D, calcium, methionine, choline, and folate induced colon cancer in the absence of a carcinogen. Studies on the chemopreventive elements in the diet indicate that many nutrients and non-nutrient components of diets are chemopreventive. We hypothesize that a diet enriched in chemopreventive factors (folate, calcium, vitamin D, and conjugated linoleic acid (CLA)) will potentiate the therapeutic ratio of FUra in the Apc Min/+ mouse. We postulate that a "cancer preventive" diet will enhance FUra-induced programmed cell death (apoptosis) in the colon, whereas a Western Stress diet will inhibit the effects of FUra treatment. In Aim 1, we will identify the molecular mechanisms by which pro-apoptotic dietary factors modulate the therapeutic efficacy of 5-fluoro-2'-deoxyuridine (FdUrd; nueleoside derivative of FUra) by examining biomarkers related to inflammation, proliferation, differentiation, and apoptosis in human colon cancer cell lines. In Aim 2, we will evaluate the therapeutic efficacy of administration of FUra on tumor incidence in the Apd Min/+ mouse. In Aim 3, we will evaluate the effects that (1) a supplemented diet enriched in folate, calcium, vitamin D, and conjugated linoleic acid and (2) a diet deficient in these factors has on 5-FU efficacy in the Apc Min/+ mouse. Results from this work will provide novel insight into the mechanisms of how dietary factors benefit colon tumorigenesis and how these dietary agents influence the ability of FUra to modulate colon carcinogenesis. Data obtained from these studies will be used to generate NIH R01 funding.